Hofbauer, Lorenz C.

Abstract Hypoparathyroidism is an endocrine disease caused by insufficient levels of PTH, which acts directly on bone and kidney and indirectly on the intestine to regulate calcium and phosphate balance. In clinical trials, palopegteriparatide (TransCon PTH) treatment enabled independence from conventional therapy (no active vitamin D, ≤600 mg/d calcium) and maintained serum biochemistries within normal ranges. The current analyses describe patterns of change in BMD, serum bone turnover markers, and serum and urine calcium in adults with chronic hypoparathyroidism treated with palopegteriparatide through 3 years of the PaTH Forward trial. Baseline BMD Z-scores for the LS, TH, FN, and 1/3 distal radius were above zero, indicating bone mass exceeding age-adjusted normative values. BMD decreased from these elevated baseline levels with palopegteriparatide treatment, with larger reductions during the first 26 weeks and modest declines thereafter. Mean BMD Z-scores at week 162 remained above zero for all 4 sites. Participants with lower baseline BMD (Z-scores below −1 and T-scores below −2.5) generally exhibited lesser declines in BMD versus those with higher baseline BMD. Palopegteriparatide treatment was associated with early increases in bone resorption (serum C-terminal telopeptide of type I collagen, CTx) and bone formation (serum procollagen type 1 N-terminal propeptide, P1NP) that peaked at weeks 12 and 26, respectively, followed by declines to levels moderately higher than baseline at week 162. Mean CTx and P1NP in the overall population and the subgroup of postmenopausal women were below their upper limits of normal from weeks 58-162. At week 162, mean serum and median urine calcium remained within normal ranges and 91% of participants were independent from conventional therapy. These results suggest that long-term palopegteriparatide therapy in adults with chronic hypoparathyroidism gradually returns the skeleton toward its natural state thereby enhancing the skeleton’s contribution to calcium homeostasis.

Abstract Disclosure: D.S. Ali: None. Z. Chung: None. L. Kamel: None. S. Björnsdottir: Shire. B.L. Clarke: Shire, Takeda, Ascendis, Calcilytix. S. Hahner: None. L.C. Hofbauer: Amgen Inc, Ascendis, UCB, Ascendis, Amolyte. P. Houillier: None. S.W. Ing: Amgen Inc, Radius Health, Inc, Takeda, AscendAlexion, Amolyt, Ascendis, Calcilytix, Kyowa Kirin. M.A. Levine: Takeda, Amolyt, Calcilytix. M. Mannstadt: Takeda, Amolyt, Calcilytix. L. Rejnmark: Takeda, Amolyt, Ascendis, Calcilytix. D.M. Shoback: Amolyt, Ascendis, member of the advisory board (PARADIGHM). M. Brandi: Takeda, Eli Lilly & Company, Calcilytix, Kyowa Kirin, UCB, Abiogen, Alexion, Amolyt, Amorphical, Bruno Farmaceutici, CoGeDi, Echolight. A.A. Khan: Takeda, Amgen Inc, Alexion, Ascendis, Amolyt, Calcilytix. Background: Hypoparathyroidism (HypoPT) is a rare endocrine disorder that requires close evaluation and follow up during pregnancy to minimize maternal and fetal complications. The primary objectives of this study are to evaluate the use of rhPTH (1-84) during pregnancy by analyzing data from the PARADIGHM disease registry, and to compare maternal and neonatal outcomes among patients who continued PTH therapy during pregnancy versus those on conventional therapy (CT). Methods: We performed a retrospective analysis of data in the PARADIGHM registry. Maternal and neonatal outcomes in women treated with rhPTH (1-84) were compared to women who received CT. Results: We analyzed 39 pregnancies of 32 women. Of those, 4 women (6 pregnancies) used rhPTH (1-84) either before or during pregnancy and 28 women (33 pregnancies) continued CT during pregnancy. The mean (SD) maternal age at enrollment was 31.7 (5.6) years. Postsurgical HypoPT was the most common etiology (68.8%). The mean gestational age at delivery was 36 (2.4) weeks (PTH-treated) vs 38.3 (3.3) weeks (CT) (p=0.162). Preterm delivery rates were higher in the PTH-treated group (50% vs. 27%, p=0.591), but this was not statistically significant. Two women had pre-eclampsia, one in each group (PTH-treated and CT). In the PTH-treated group, one pregnancy resulted in a stillbirth, and one infant was born with congenital anomalies (16.7% each). Conclusions: The safety of rhPTH (1-84) use in pregnancy cannot be determined at this time. The PTH-treated group exhibited trends towards higher rates of preterm delivery, but the rates of stillbirth, and congenital anomalies were low and comparable in both groups of women. Larger studies are necessary to determine the optimal approach to manage women with HypoPT during pregnancy. Presentation: Sunday, July 13, 2025

Abstract Context Conventional therapy for hypoparathyroidism aims to alleviate symptoms of hypocalcemia but does not address insufficient parathyroid hormone (PTH) levels. Objective Assess the long-term efficacy and safety of TransCon PTH (palopegteriparatide) for hypoparathyroidism. Design Phase 3 trial with a 26-week, double-blind, placebo-controlled period followed by a 156-week, open-label extension (OLE). Setting Twenty-one sites across North America and Europe. Participants A total of 82 adults with hypoparathyroidism were randomized and received study drug and 78 completed week 52. Intervention(s) All OLE participants received TransCon PTH administered once daily. Main Outcome Measure(s) Multicomponent efficacy endpoint: proportion of participants at week 52 who achieved normal serum calcium (8.3-10.6 mg/dL) and independence from conventional therapy (≤600 mg/day of elemental calcium and no active vitamin D). Other efficacy endpoints included patient-reported outcomes and bone mineral density. Safety was assessed by 24-hour urine calcium and treatment-emergent adverse events. Results At week 52, 81% (63/78) met the multicomponent efficacy endpoint, 95% (74/78) achieved independence from conventional therapy, and none required active vitamin D. Patient-reported outcomes showed sustained improvements in quality of life, physical functioning, and well-being. Mean bone mineral density Z-scores decreased toward age- and sex-matched norms from baseline to week 52. Mean (SD) 24-hour urine calcium excretion decreased from 376 (168) mg/day at baseline to 195 (114) mg/day at week 52. Most treatment-emergent adverse events were mild or moderate and none led to trial discontinuation during the OLE. Conclusion At week 52 of the PaTHway trial, TransCon PTH showed sustained efficacy, safety, and tolerability in adults with hypoparathyroidism.

Abstract Disclosure: B. Clarke: Advisory Board Member; Self; Ascendis Pharma, Takeda, Entera-Bio, Extend-Bio, Amolyt. Consulting Fee; Self; Ascendis Pharma, Takeda, Entera-Bio, Extend-Bio, Amolyt. Grant Recipient; Self; Ascendis Pharma, Takeda. Research Investigator; Self; Ascendis Pharma, Takeda. Other; Self; Ascendis Pharma, Takeda, Entera-Bio, Extend-Bio, Amolyt. A.A. Khan: Advisory Board Member; Self; Amgen Inc, Alexion Pharmaceuticals, Inc., Ascendis Pharma, Takeda, Ultragenyx. Consulting Fee; Self; Amgen Inc, Alexion Pharmaceuticals, Inc., Amolyt, Ascendis Pharma, Ultragenyx. Grant Recipient; Self; Amolyt. Research Investigator; Self; Radius Health, Inc, Takeda, Ultragenyx, Amolyt, Ascendis Pharma, Chugai. Speaker; Self; Amgen Inc. Other; Self; Amgen Inc, Alexion Pharmaceuticals, Inc., Ascendis Pharma, Takeda, Ultragenyx. M.R. Rubin: Research Investigator; Self; Chugai Pharma. P.E. Schwarz: Stock Owner; Self; Novo Nordisk, Genmab. T.J. Vokes: Consulting Fee; Self; Takeda, Ascendis Pharma. Research Investigator; Self; Ascendis Pharma, Radius Health, Inc. D.M. Shoback: Research Investigator; Self; Bone Health Tech. C. Gagnon: Advisory Board Member; Self; Novo Nordisk. Grant Recipient; Self; Shire, Takeda, Ascendis Pharma. Research Investigator; Self; Novo Nordisk. Other; Self; Amgen Inc. A. Palermo: Consulting Fee; Self; Theramex, Bruno, Farmaceutici, Amgen Inc. Grant Recipient; Self; Amgen Inc. Research Investigator; Self; Amgen Inc, Shire, Ascendis Pharma. Speaker; Self; UCB, Amgen Inc. L.G. Abbott: Advisory Board Member; Self; Ascendis. Research Investigator; Self; Takeda, Shire, Ascendis Pharma. Speaker; Self; Abbott Laboratories, Clarus. Other; Self; Ascendis. L.C. Hofbauer: Advisory Board Member; Self; Amgen Inc, UCB. Other; Self; Amgen Inc, UCB. L. Kohlmeier: Advisory Board Member; Self; Alexion Pharmaceuticals, Inc., Ascendis Pharma. Research Investigator; Self; Ascendis Pharma. Speaker; Self; Amgen Inc, Radius Health, Inc, Alexion Pharmaceuticals, Inc., Ascendis Pharma. Other; Self; Amgen Inc, Radius Health, Inc, Alexion Pharmaceuticals, Inc., Ascendis Pharma, MediMaps. F. Cetani: None. S. Phil: Employee; Self; Ascendis Pharma. X. An: Employee; Self; Ascendis Pharma. A.R. Smith: Employee; Self; Ascendis Pharma. B. Lai: Employee; Self; Ascendis Pharma. J. Le: Employee; Self; Ascendis Pharma. J. Ukena: Employee; Self; Ascendis Pharma. C. Sibley: Employee; Self; Ascendis Pharma. A. Shu: Employee; Self; Ascendis Pharma. L. Rejnmark: Advisory Board Member; Self; Takeda, Amolyt. Research Investigator; Self; Takeda, Kyowa Kirin International, Ascendis Pharma, Calcilytix Therapeutics. Other; Self; Calcilytix Therapeutics. Objective: Evaluate the long-term efficacy and safety of TransCon PTH as a potential hormone replacement therapy for hypoparathyroidism. Methods: PaTHway is a phase 3 trial of TransCon PTH with a placebo (PBO)-controlled 26-week blinded period and a 156-week open-label extension (OLE) period. Results through Week 52 (26 weeks blinded + 26 weeks OLE) are reported. Three-component efficacy endpoint: normal serum calcium (8.3-10.6 mg/dL) and independence from conventional therapy (≤600 mg/day of elemental calcium and no active vitamin D). Other endpoints: Hypoparathyroidism Patient Experience Scale (HPES); 36-Item Short Form Survey (SF-36); bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA); bone turnover markers (BTM) procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTx). Safety was assessed by 24-hour urine calcium and reported treatment-emergent adverse events (TEAEs). Results: Of the 82 participants given study drug, 79 completed blinded treatment and entered the OLE, and 78 (59 TransCon PTH/TransCon PTH, 19 PBO/TransCon PTH) completed Week 52. Overall at Week 52, 81% (63/78) met the efficacy endpoint, 95% (74/78) achieved independence from conventional therapy, and none required active vitamin D. Mean albumin-adjusted serum calcium was within the normal range at all time points in the OLE (8.9 mg/dL at Week 52). Mean Week 52 HPES scores showed sustained improvement from baseline in disease-related symptoms and the impact of hypoparathyroidism on physical functioning and daily life. Mean Week 52 SF-36 physical functioning scores also remained above baseline. In the TransCon PTH/TransCon PTH group, mean BMD corrected Z-scores trended toward norms from baseline to Weeks 26 and 52:1.5, 0.7, 0.7 at the lumbar spine (L1-L4); 0.8, 0.3, 0.3 at femoral neck; 0.9, 0.5, 0.4 at total hip; and 0.3, 0.3, 0.3 at distal 1/3 radius; P1NP peaked at Week 26 and CTx at Week 12. Smaller incremental changes were seen in BMD and BTM from Weeks 26 to 52 than baseline to Week 26. In the PBO/TransCon PTH group, changes in BMD and BTM from Week 26 to 52 resembled those in the TransCon PTH/TransCon PTH group from baseline to Week 26. Mean 24-hour urine calcium excretion decreased from 376 mg/day at baseline to 195 mg/day at Week 52. Most TEAEs were mild or moderate and none led to discontinuation of the study drug or trial. Conclusions: At Week 52 of the PaTHway trial, TransCon PTH showed a similar sustained efficacy, safety, and tolerability profile to that of Week 26, demonstrating its potential as a hormone replacement therapy for adults with hypoparathyroidism. Indices of skeletal dynamics trended toward age- and sex-matched norms in the TransCon/TransCon PTH group. TransCon PTH treatment in the PBO/TransCon PTH group showed rapid improvement in all outcomes in the first 26 weeks of the OLE consistent with the pattern in the TransCon PTH group during the blinded period. Presentation: Saturday, June 17, 2023

ABSTRACT Conventional therapy for hypoparathyroidism consisting of active vitamin D and calcium aims to alleviate hypocalcemia but fails to restore normal parathyroid hormone (PTH) physiology. PTH replacement therapy is the ideal physiologic treatment for hypoparathyroidism. The double-blind, placebo-controlled, 26-week, phase 3 PaTHway trial assessed the efficacy and safety of PTH replacement therapy for hypoparathyroidism individuals with the investigational drug TransCon PTH (palopegteriparatide). Participants (n = 84) were randomized 3:1 to once-daily TransCon PTH (initially 18 μg/d) or placebo, both co-administered with conventional therapy. The study drug and conventional therapy were titrated according to a dosing algorithm guided by serum calcium. The composite primary efficacy endpoint was the proportion of participants at week 26 who achieved normal albumin-adjusted serum calcium levels (8.3–10.6 mg/dL), independence from conventional therapy (requiring no active vitamin D and ≤600 mg/d of calcium), and no increase in study drug over 4 weeks before week 26. Other outcomes of interest included health-related quality of life measured by the 36-Item Short Form Survey (SF-36), hypoparathyroidism-related symptoms, functioning, and well-being measured by the Hypoparathyroidism Patient Experience Scale (HPES), and urinary calcium excretion. At week 26, 79% (48/61) of participants treated with TransCon PTH versus 5% (1/21) wiplacebo met the composite primary efficacy endpoint (p < 0.0001). TransCon PTH treatment demonstrated a significant improvement in all key secondary endpoint HPES domain scores (all p < 0.01) and the SF-36 Physical Functioning subscale score (p = 0.0347) compared with placebo. Additionally, 93% (57/61) of participants treated with TransCon PTH achieved independence from conventional therapy. TransCon PTH treatment normalized mean 24-hour urine calcium. Overall, 82% (50/61) treated with TransCon PTH and 100% (21/21) wiplacebo experienced adverse events; most were mild (46%) or moderate (46%). No study drug-related withdrawals occurred. In conclusion, TransCon PTH maintained normocalcemia while permitting independence from conventional therapy and was well-tolerated in individuals with hypoparathyroidism. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). Abstract TransCon PTH is an investigational once-daily prodrug providing sustained release of active PTH designed to maintain stable PTH levels in the physiological range for 24 hours/day. The PaTHway trial met all primary and key secondary endpoints with statistically significant differences from placebo. Most adverse events (AEs) were mild/moderate. Injection-site reactions and headaches were the most common treatment-related AEs.

ABSTRACT In this narrative review, we present data gathered over four decades (1980–2020) on the epidemiology, pathophysiology and genetics of primary hyperparathyroidism (PHPT). PHPT is typically a disease of postmenopausal women, but its prevalence and incidence vary globally and depend on a number of factors, the most important being the availability to measure serum calcium and parathyroid hormone levels for screening. In the Western world, the change in presentation to asymptomatic PHPT is likely to occur, over time also, in Eastern regions. The selection of the population to be screened will, of course, affect the epidemiological data (ie, general practice as opposed to tertiary center). Parathyroid hormone has a pivotal role in regulating calcium homeostasis; small changes in extracellular Ca++ concentrations are detected by parathyroid cells, which express calcium-sensing receptors (CaSRs). Clonally dysregulated overgrowth of one or more parathyroid glands together with reduced expression of CaSRs is the most important pathophysiologic basis of PHPT. The spectrum of skeletal disease reflects different degrees of dysregulated bone remodeling. Intestinal calcium hyperabsorption together with increased bone resorption lead to increased filtered load of calcium that, in addition to other metabolic factors, predispose to the appearance of calcium-containing kidney stones. A genetic basis of PHPT can be identified in about 10% of all cases. These may occur as a part of multiple endocrine neoplasia syndromes (MEN1–MEN4), or the hyperparathyroidism jaw-tumor syndrome, or it may be caused by nonsyndromic isolated endocrinopathy, such as familial isolated PHPT and neonatal severe hyperparathyroidism. DNA testing may have value in: confirming the clinical diagnosis in a proband; eg, by distinguishing PHPT from familial hypocalciuric hypercalcemia (FHH). Mutation-specific carrier testing can be performed on a proband's relatives and identify where the proband is a mutation carrier, ruling out phenocopies that may confound the diagnosis; and potentially prevention via prenatal/preimplantation diagnosis. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). Abstract The prevalence and incidence of PHPT vary around the world and depend on a number of factors, the most important being availability of serum calcium (and parathyroid hormone) measurement for screening, which in the Western world has shifted its presentation to an asymptomatic disorder. Clonally dysregulated overgrowth of one or more parathyroid glands together with reduced expression of CaSRs is the most important pathophysiologic basis of PHPT, which may also occur as a part of inherited syndromes or as a nonsyndromic isolated endocrinopathy in 10% of cases. Genetic testing has roles in establishing the clinical diagnosis, although its value requires assessments using GRADE(176) methodology, which is recommended for future consideration.

Abstract Context Hypoparathyroidism is characterized by insufficient levels of parathyroid hormone (PTH). TransCon PTH is an investigational long-acting prodrug of PTH(1-34) for the treatment of hypoparathyroidism. Objective This work aimed to investigate the safety, tolerability, and efficacy of daily TransCon PTH in adults with hypoparathyroidism. Methods This phase 2, randomized, double-blind, placebo-controlled 4-week trial with open-label extension enrolled 59 individuals with hypoparathyroidism. Interventions included TransCon PTH 15, 18, or 21 µg PTH(1-34)/day or placebo for 4 weeks, followed by a 22-week extension during which TransCon PTH dose was titrated (6-60 µg PTH[1-34]/day). Results By Week 26, 91% of participants treated with TransCon PTH achieved independence from standard of care (SoC, defined as active vitamin D = 0 μg/day and calcium [Ca] ≤ 500 mg/day). Mean 24-hour urine Ca (uCa) decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while normal serum Ca (sCa) was maintained and serum phosphate and serum calcium-phosphate product fell within the normal range. By Week 26, mean scores on the generic 36-Item Short Form Health Survey domains increased from below normal at baseline to within the normal range. The Hypoparathyroidism Patient Experience Scale symptom and impact scores improved through 26 weeks. TransCon PTH was well tolerated with no treatment-related serious or severe adverse events. Conclusion TransCon PTH enabled independence from oral active vitamin D and reduced Ca supplements (≤ 500 mg/day) for most participants, achieving normal sCa, serum phosphate, uCa, serum calcium-phosphate product, and demonstrating improved health-related quality of life. These results support TransCon PTH as a potential hormone replacement therapy for adults with hypoparathyroidism.

Abstract Background: Hypoparathyroidism (HP) is characterized by insufficient levels of parathyroid hormone (PTH), resulting in hypocalcemia, hyperphosphatemia, hypercalciuria, and a reduced quality of life (QoL). PTH replacement therapy should restore physiologic levels of PTH and restore downstream physiologic levels of calcitriol, promoting independence from Ca and active vitamin D supplements and normalization of QoL. TransCon PTH is an investigational long-acting prodrug of PTH(1–34) for the treatment of HP. During the initial 4-week fixed-dose period of the PaTH Forward Trial, TransCon PTH enabled 82% of subjects to achieve independence from standard of care (SoC; no active vitamin D and Ca ≤ 500 mg/day) compared to 15% with placebo. Here, we report 6-month (Week 26) results from the open-label extension (OLE). Methods: PaTH Forward is a phase 2, double-blind, placebo-controlled trial evaluating TransCon PTH in adult HP patients treated with SoC. Subjects received fixed doses of TransCon PTH 15, 18, or 21 µg PTH(1–34)/day or placebo for 4 weeks, followed by an OLE period during which TransCon PTH dose was titrated (6–30 µg PTH[1–34]/day) per individual dosing requirement. Safety and efficacy endpoints were evaluated at predefined timepoints over the OLE. Endpoints were evaluated at Week 26 including 1) sCa, 2) 24-hour uCa, 3) independence from active vitamin D, and 4) independence from therapeutics doses of oral calcium. QoL was assessed by the SF-36 and the Hypoparathyroidism Patient Experience Scales (HPES). Results: All 59 subjects completed the initial 4-week period and continued in the OLE; 58 subjects continue in the OLE beyond 6 months (1 withdrew unrelated to safety or efficacy). TransCon PTH enabled independence from SoC (no active vitamin D and Ca ≤ 500 mg/day) in 91% of subjects and independence from all supplements (no active vitamin D and no Ca) in 76% of subjects by Week 26. Mean 24-hour uCa decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while maintaining sCa, and reducing sP and CaxP to fall within the normal range. The mean scores for all SF-36 summary and domains increased from below normal at baseline to within the normal range by Week 26. The HPES Symptom and Impact scores continuously improved through 26 weeks for TransCon PTH and placebo subjects switching to TransCon PTH. TransCon PTH continued to be well-tolerated with no treatment-related serious or severe adverse events. Conclusions: Results from the OLE of the PaTH Forward Trial demonstrated that TransCon PTH continued to enable independence from active vitamin D and Ca supplements for most subjects while maintaining normal sCa, sP, uCa, and demonstrating enhanced quality of life, supporting its potential as a hormone replacement therapy for patients with HP. TransCon PTH will be further evaluated in the phase 3 PaTHway Trial.

Abstract PARADIGHM is an actively recruiting, prospective, observational registry (NCT01922440/EUPAS16927). The primary objective is to evaluate the safety and effectiveness of recombinant human parathyroid hormone, rhPTH(1-84), treatment in patients with chronic hypoparathyroidism (HypoPT) under routine clinical care. The secondary objective is to characterize the clinical course of chronic HypoPT under conditions of routine clinical practice. At enrollment, registry inclusion criteria are patients having a HypoPT diagnosis >6 months and receiving conventional therapy (CT; eg, calcium supplements and active vitamin D), rhPTH(1-84) plus CT, or rhPTH(1-84). We present baseline characteristics of patients as of a June 30 2019 data cut. Baseline was defined as the value entered at the time of enrollment (Visit 1). Baseline symptom data exclude patients who initiated rhPTH(1-84) prior to enrollment (n=68) and are herein presented as two groups: those subsequently prescribed with rhPTH(1-84) after enrollment or those treated with CT. All data are summarized descriptively. Patient data from 64 centers in Europe and North America were analyzed. In the analysis population (n=737), 587 patients (79.6%) were female, 620 (84.1%) were white, and the mean (SD) age was 49.1 (16.45) years. The mean (SD) BMI was 19.3 (5.73) kg/m2 and 30.0 (7.72) kg/m2 in patients aged <18 (n=25) and ≥18 (n=587) years, respectively. The primary cause of HypoPT was thyroid surgery (n=547 [74.2%]; of these, 281 [60.0%] underwent surgery for thyroid cancer). Endocrinologists were the prescribing specialists for most patients (n=660 [89.6%]). Vitamin D and analogs were prescribed for 90.1% of patients (calcitriol, 74.2%, native vitamin D, 47.4%, alfacalcidol, 7.9%,), calcium for 81.0% (calcium carbonate, 57.9%, calcium citrate, 27.1%), and thyroid hormones for 71.2% (levothyroxine, 73.4%; liothyronine, 5.8%). Symptoms reported at enrollment for the rhPTH(1-84) (n=66) and the CT groups (n=603), respectively, included fatigue (53.0%, 39.3%), paresthesia (48.5%, 29.2%), muscle twitching (48.5%, 21.1%), muscle cramping (40.9%, 33.0%), headaches (33.3%, 17.6%), anxiety (28.8%, 20.1%), muscle pain (28.8%, 19.2%), tetany (28.8%, 12.1%), and brain fog (27.3%, 16.3%). The baseline data for the overall population appear to be representative of patients with chronic HypoPT. Baseline data suggest that at enrollment patients prescribed rhPTH(1-84) after enrollment appear to have an increased burden of disease than patients receiving CT based on symptoms. PARADIGHM will be a valuable resource of real-world longitudinal data for patients with chronic HypoPT.

Abstract Background: Hypoparathyroidism (HP) is caused by a deficiency in parathyroid hormone (PTH), which leads to hypocalcemia and hyperphosphatemia. Standard of care (SoC), i.e. large doses of calcium (Ca) and active vitamin D, worsens hypercalciuria and increases the serum Ca (sCa) x serum phosphate (sP) product. Studies have shown that continuous subcutaneous infusion of PTH(1-34) normalizes sCa, sP, serum magnesium, urine Ca (uCa) and bone turnover better than SoC or once- or twice-daily injections of PTH in HP patients. TransCon PTH, an investigational long-acting prodrug of PTH (1-34) transiently bound to an inert carrier via a linker, is under development as a potential once-daily replacement therapy for HP. Under physiological conditions, linker auto-cleavage occurs, releasing active PTH at a controlled rate with ~60 hour half-life. Phase 1 trial results demonstrated that once-daily TransCon PTH provided a flat, infusion like profile within the normal range of PTH 24 hours per day, increasing sCa while controlling uCa and decreasing sP, with no evidence of bone anabolic activity. Phase 2 Design: PaTH Forward is a global phase 2 trial evaluating the safety, tolerability, and efficacy of TransCon PTH in adult subjects with HP. Patients with HP treated with SoC were randomized at sites worldwide to daily TransCon PTH 15, 18 or 21 µg PTH(1-34) or daily blinded placebo via pen-injector for 4 weeks. The primary composite endpoint requires 1) normal albumin-adjusted sCa, and 2) normal Fractional Excretion of Ca (or ≥50% decrease from baseline), and 3) not taking active D, and 4) taking ≤1000 mg/d of Ca. After four weeks, all subjects enter an open-label extension period with the opportunity to receive TransCon PTH individually optimized to doses of 6 to 30 µg daily to evaluate long-term safety and efficacy. Other endpoints include the impact of treatment on patient experience, CaxP product, bone turnover markers, and bone mass by DXA and TBS to confirm the lack of anabolic effect. Preliminary Results: Approximately 55 subjects are expected to be randomized and dosed. Preliminary diary data on the initial 8 subjects completing 4 weeks of follow-up in the extension trial shows that all have discontinued SoC. Additional information will be presented at ENDO 2020. The Phase 2 trial is designed to inform the starting dose for a global pivotal phase 3 trial and evaluate TransCon PTH as a “true” PTH replacement therapy.